Great effort has been invested in the study of the pituitary responses to various stimuli in patients with psychiatric illnesses. This approach is based upon the assumption that hormonal changes in these patients may reflect some underlying neurochemical disturbance which is peculiar to depression or other psychiatric illness. Changes in pituitary-adrenal regulations, as disclosed by the 1 mg dexamethasone suppression test, have received particular attention in depression because of their frequency and reproducibility. Little has been done to understand the mechanism of abnormal pituitary adrenal regulation or the mechanisms of the dexamethasone suppression test as it is used in this setting. Our preliminary results have led us to question some traditional assumptions concerning pituitary ACTH regulation and the mechanism of dexamethasone action. This proposal seeks to test several elements that contribute to a nontraditional model of pituitary-adrenal regulation. Based upon preliminary work, we wish to study healthy subjects to examine: 1) Whether there is heterogeneity of circulating immunoreactive ACTH and/or alterations in the ratio of immunoreactive/bioactive hormone in health and depressed subjects. 2) Whether the temporal relationship between plasma levels of ACTH and cortisol can be desynchronized by sleep deprivation. 3) Whether there are time-related (circadian) changes in the pituitary response to ACTH secretogogues and/or the adrenal response to endogenous and exogenous ACTH. 4) Whether endogenous and exogenous glucocorticoids participate directly in adrenal regulation (autoregulation), particularly whether dexamethasone has a direct effect on the adrenal to decrease its sensitivity to ACTH. Results of these studies should lead to the formulation of more incisive strategies for the understanding of endocrine dysfunction in depressed patients.